The long-term overall goal of this Specialized Program of Translational Research in Acute Stroke (SPOTRIAS) is to improve the early recanalization of occluded arteries in patients with acute ischemic stroke without compromising safety. The unifying theme of our three projects is the development of new recanalization strategies and markers of outcomes and risk in patients with acute ischemic stroke. In Project 1, Drs. Pancioli, Brokerick, Brott, and co-investigators will initiate a double-blind, randomized, dose-finding safety trial of combined lower dose intravenous rt-PA and intravenous eptifibatide (a GP-IIb/IIIa platelet receptor antagonist) as compared to standard dose -tPa administered within 3 hours of onset of ischemic stroke (The CLEAR STROKE Trial). In Project 2 Drs. Jauch, Wagner, Hilliard, and co-investigators will use serum samples from the 100 patients in the CLEAR TRIAL to investigate the relationship of serum protein markers (S-100 protein and myelin basic protein to functional and radiographic outcomes. In addition, an initial proteomics approach will be applied to serum samples from patients in the CLEAR Trial, with and without ICH, to explore and identify new serum protein markers related to the development of ICH following recanalization therapy. In Project Dr. Sharp and co-investigators will measure genomic expression in blood lymphocytes and determine whether there is a specific genomic expression profile of patients with ischemic stroke, patients with spontaneous ICH, and ischemic stroke patients who have ICH following treatment with t-PA and/or eptifibatide as part of the CLEAR trial. The Patient Access and Administrative Core, Core A, directed by Drs. Broderick, will support those administrative functions necessary to insure the successful performance and integration of the three research projects. The Career Development Core, Core C, will oversee the clinical research training and career development of identified physicians who are committed to becoming independent clinical researchers in the area of cerebrovascular disease and acute stroke. The Blood and Tissue Specimen Core, Core D, will oversee the collection, storage, and distribution of serum and blood samples to respective laboratories for analysis. We are confident that these projects will lead to better and safer therapy for patients with acute ischemic stroke.